A FAMILY'S INHERITANCE

For most expectant parents, part of the fun is wondering which traits will get passed down to your children. Will they have their father’s nose? Their mother’s eyes?

For one Iowa family, there’s a different trait to worry about. Sixty-one members of Jerry Jackson’s family1 have been diagnosed with ADNIV (autosomal dominant neovascular inflammatory vitreoretinopathy), an extremely rare genetic disease that eventually leads to blindness. Jackson himself started getting vision problems in his 20s, and when a cousin developed similar symptoms, doctors began suspecting a genetic cause. Eventually, the genetic mutation was traced back through generations of the family’s Scottish ancestry.2 Today, at 68 years old, Jerry Jackson is completely blind.2 Both his daughters were diagnosed with ADNIV,1 and since it’s an autosomal dominant disorder, all his grandchildren have a 50% chance of becoming blind. Unfortunately, much remains unknown about the disease.

An autoimmune disorder, ADNIV causes inflammation and bleeding in the eye, and is characterized by progressive stages that mimic other eye diseases. This means that studying ADNIV could help with other (more common) disorders, but for ADNIV patients, it also means that they pretty much experience a mash-up of multiple horrible diseases:3

In 2012, scientists finally identified the genetic mutation that causes ADNIV. Amongst three families with ADNIV (including Jerry Jackson’s), all patients had a mutation in the CAPN5 gene.3CAPN5encodes the protein Calpain-5, a calcium-activated protease with a currently unknown physiological function.3

In general, the Calpain family proteins are known to target multiple intracellular proteins and pathways, and unlike other proteases, are not involved in protein degradation. Instead, they can modulate the structure (and thus activity) of their target substrates.4 Being highly conserved enzymes, calpains are found in most eukaryotes, and defects in these proteins can have severe effects including lethality.4 Given that calpains typically have diverse target substrates, it may be unsurprising that CAPN5 has also been implicated in other diseases like endometriosis5 and polycystic ovary syndrome.6 After all, it is expressed in a variety of tissues including the colon, kidney, liver, trachea, uterus, eye, and brain.3 Still, we don’t know which proteins CAPN5 interacts with, in any of these tissues.

Even so, scientists have found a way to potentially treat ADNIV. Instead of targeting specific signaling pathways (since we don’t know them), doctors are taking the general approach of treating inflammation, and thus, its negative consequences. Some ADNIV patients have already received an implant that continuously releases corticosteroids within the eye, which has been shown to reduce inflammation and neovascularization.7 The surgical implant works best when implemented early in disease progression, and while it’s too soon to tell, doctors are hopeful that it could slow vision loss, and perhaps even allow ADNIV patients to permanently retain central, if not peripheral, vision.7

No, these aren't abstract drawings... they're diagrams of eyes from two ADNIV patients that received implants. Note the pervasive presence of neovascularization, fibrosis, and areas of retinal detachment. [Source: Tlucek et al. (2012)]

Of course, this new treatment offers a considerable amount of hope to all ADNIV patients. As for Jerry Jackson himself, he hasn’t let blindness disable him; he still works as a bicycle mechanic (in addition to his job at the grocery store), and enjoys long bicycle rides—on both a tandem bike, and occasionally, even solo!1 His 25-year-old granddaughter, Bobbi Boline, also has the ADNIV gene variant, but having seen her grandfather living a full life, has said, “I’m OK with it.”1 As Jackson’s daughter has said, “[Blindness] never stopped him from anything. He just went and went and went.”1